The present invention relates to processes for the preparation of 3,5-bis(trifluoromethyl)bromobenzene (CAS 328-70-1) which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The preparation of 3,5-bis(trifluoromethyl)bromobenzene by bromination of 1,3-bis(trifluoromethyl)benzene has been described various references. See for example: (a) Porwisiak, J; Schlosser, M. Chem. Ber., 129(2), 233 (1996); (b) Kunshenko, B. V.; Omarov, V. O.; Muratov, N. N.; Mikhailevskii, S. M.; Yagupol'skii, L. M. Zh. Org. Khim., 27(1), 125 (1991); (c) Larionova, Y. A.; Ponomarev, A. I.; Klebanskii, A. L.; Zaitsev, N. B.; Kol'tsov, A. I.; Motsarev, G. V.; Rozenberg, V. R. Zh. Prikl. Khim., 46(9), 2012 (1973); (d) Furumata, T. (Central Glass Company, Ltd.) JP 9067297-A2 [J09067297] 97.03.11; Filing Date Aug. 28, 1995; (e) Suzuki, H. (Nissan Chemical Industries, Ltd., Japan) JP 9169673-A2 [J09169673] 97.06.30 Heisei; Filing Date Dec. 22, 1995. These references describe the preparation of 3,5-bis(trifluoromethyl)bromobenzene by brominating 1,3-bis(trifluoromethyl)benzene utilizing either N-bromosuccinimide (NBS) or 1,3-dibromo-5,5-dimethylhydantoin (DBH) in sulfuric acid or trifluoroacetic acid. The yields are quoted in the 90% range with isomeric and bis-brominated byproducts amounting to 5-10%. Efforts to repeat the procedures using methods with sulfuric acid as disclosed therein led to inconsistent yields of the desired product.
The general processes disclosed in the art for the preparation of 3,5-bis(trifluoromethyl)bromobenzene result in relatively low and inconsistent yields of the desired product. In contrast to the previously known processes, the present invention provides effective methodology for the preparation of 3,5-bis(trifluoromethyl)bromobenzene in relatively higher yield.
In accordance with the present invention, the use of acetic acid and/or a faster rate of stirring for the bromination of 1,3-bis(trifluoromethyl)benzene in sulfuric acid results in a more selective bromination of the starting material with higher yields of the product and lower amounts of bis-brominated byproducts.
It will be appreciated that 3,5-bis(trifluoromethyl)bromobenzene is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of 3,5-bis-(trifluoromethyl)bromobenzene which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of 3,5-bis(trifluoromethyl)bromobenzene via a very simple, short and highly efficient synthesis.